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https://www.readbyqxmd.com/read/28536305/shaping-the-tumor-stroma-and-sparking-immune-activation-by-cd40-and-4-1bb-signaling-induced-by-an-armed-oncolytic-virus
#1
Emma Eriksson, Ioanna Milenova, Jessica Wenthe, Magnus Ståhle, Justyna Leja-Jarblad, Gustav Ullenhag, Anna Dimberg, Rafael Moreno, Ramon Alemany, Angelica Loskog
PURPOSE: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activate the CD40 and 4-1BB pathways, respectively...
May 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28523432/novel-t-cells-with-improved-in-vivo-anti-tumor-activity-generated-by-rna-electroporation
#2
Xiaojun Liu, Shuguang Jiang, Chongyun Fang, Hua Li, Xuhua Zhang, Fuqin Zhang, Carl H June, Yangbing Zhao
The generation of T cells with maximal anti-tumor activities will significantly impact the field of T-cell-based adoptive immunotherapy. In this report, we found that OKT3/IL-2-stimulated T cells were phenotypically more heterogeneous, with enhanced anti-tumor activity in vitro and when locally administered in a solid tumor mouse model. To further improve the OKT3/IL-2-based T cell manufacturing procedure, we developed a novel T cell stimulation and expansion method in which peripheral blood mononuclear cells were electroporated with mRNA encoding a chimeric membrane protein consisting of a single-chain variable fragment against CD3 and the intracellular domains of CD28 and 4-1BB (OKT3-28BB)...
May 18, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28521477/t-cell-immunity-induced-by-a-bivalent-salmonella-based-ceacam6-and-4-1bbl-vaccines-in-a-rat-colorectal-cancer-model
#3
Chunhui Jin, Xiaoqing Duan, Yingying Liu, Jianhong Zhu, Ke Zhang, Yuanting Zhang, Tingting Xia, Yajun Fei, Jianxin Ye
The present study investigated the anti-tumor mechanisms of recombinant non-specific cross-reacting antigen (CEACAM6) and 4-1BB ligand (4-1BBL) Salmonella-based vaccines, and the effect that these vaccinations have on memory T cells and T helper (Th) cell polarization. Colon tumors were induced in rats via 1,2-dimethylhydrazine (DMH) injections. Rats were then treated with injections of attenuated Salmonella typhimurium carrying pIRES-CEACAM6, pIRES-4-1BBL or pIRES-CEACAM6-4-1BBL. In total, 4 vaccine injections, one every other week, were administered during the 8 weeks subsequent to the DMH injection...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28515726/comparative-analysis-of-immune-checkpoint-molecules-and-their-potential-role-in-the-transmissible-tasmanian-devil-facial-tumor-disease
#4
Andrew S Flies, Nicholas B Blackburn, Alan Bruce Lyons, John D Hayball, Gregory M Woods
Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28503098/absence-of-4-1bb-reduces-obesity-induced-atrophic-response-in-skeletal-muscle
#5
Ngoc Hoan Le, Chu-Sook Kim, Thai Hien Tu, Byung-Sam Kim, Taesun Park, Jung Han Yoon Park, Tsuyoshi Goto, Teruo Kawada, Tae Youl Ha, Rina Yu
Obesity-induced inflammation causes skeletal muscle atrophy accompanied by disruption of oxidative metabolism and is implicated in metabolic complications such as insulin resistance and type 2 diabetes. We previously reported that 4-1BB, a member of the tumor necrosis factor receptor superfamily, participated in obesity-induced skeletal muscle inflammation. Here, we show that the absence of 4-1BB in obese mice fed a high-fat diet led to a decrease in expression of atrophic factors (MuRF1 and Atrogin-1) with suppression of NF-κB activity, and that this was accompanied by increases in mitochondrial oxidative metabolic genes/proteins (e...
2017: Journal of Inflammation
https://www.readbyqxmd.com/read/28501941/paracrine-release-of-il-2-and-anti-ctla-4-enhances-the-ability-of-artificial-polymer-antigen-presenting-cells-to-expand-antigen-specific-t-cells-and-inhibit-tumor-growth-in-a-mouse-model
#6
Lei Zhang, Limin Wang, Khawar Ali Shahzad, Tao Xu, Xin Wan, Weiya Pei, Chuanlai Shen
Accumulating evidence indicates that bead-based artificial antigen-presenting cells (aAPCs) are a powerful tool to induce antigen-specific T cell responses in vitro and in vivo. To date, most conventional aAPCs have been generated by coupling an antigen signal (signal 1) and one or two costimulatory signals, such as anti-CD28 with anti-LFA1 or anti-4-1BB (signal 2), onto the surfaces of cell-sized or nanoscale magnetic beads or polyester latex beads. The development of a biodegradable scaffold and the combined use of multiple costimulatory signals as well as third signals for putative clinical applications is the next step in the development of this technology...
May 13, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28473315/4-1bb-enhanced-expansion-of-cd8-til-from-triple-negative-breast-cancer-unveils-mutation-specific-cd8-t-cells
#7
Michiko Harao, Marie-Andrée Forget, Jason Roszik, Hui Gao, Gildy V Babiera, Savitri Krishnamurthy, Jessica A Chacon, Shumin Li, Elizabeth A Mittendorf, Sarah M DeSnyder, Korrene F Rockwood, Chantale Bernatchez, Naoto T Ueno, Laszlo G Radvanyi, Luis Vence, Cara Haymaker, James M Reuben
Triple negative breast cancer (TNBC) highly infiltrated with CD8(+) tumor-infiltrating lymphocytes (TILs) has been associated with improved prognosis. This observation led us to hypothesize that CD8(+) TIL could be utilized in autologous adoptive cell therapy for TNBC, although this concept has proven to be challenging, given the difficulty in expanding CD8(+) TILs in solid cancers other than melanoma. To overcome this obstacle, we used an agonistic antibody  (urelumab) to a TNFR family member, 4-1BB/CD137, which is expressed by recently activated CD8(+) T cells...
May 4, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28415754/gene-modified-nk-92mi-cells-expressing-a-chimeric-cd16-bb-%C3%AE-or-cd64-bb-%C3%AE-receptor-exhibit-enhanced-cancer-killing-ability-in-combination-with-therapeutic-antibody
#8
Ying Chen, Fengtao You, Licui Jiang, Jialu Li, Xuejun Zhu, Yangyi Bao, Xiang Sun, Xiaowen Tang, Huimin Meng, Gangli An, Bozhen Zhang, Lin Yang
Natural killer (NK) cells play a pivotal role in monoclonal antibody-mediated immunotherapy through the antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. NK-92MI is an interleukin-2 (IL-2)-independent cell line, which was derived from NK-92 cells with superior cytotoxicity toward a wide range of tumor cells in vitro and in vivo. Nonetheless, the Fc-receptor (CD16) that usually mediates ADCC is absent in NK-92 and NK-92MI cells. To apply NK-92MI cell-based immunotherapy to cancer treatment, we designed and generated two chimeric receptors in NK-92MI cells that can bind the Fc portion of human immunoglobulins...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28381173/mesothelin-targeting-chimeric-antigen-receptor-modified-t-cells-by-piggybac-transposon-system-suppress-the-growth-of-bile-duct-carcinoma
#9
Jie-Ying Xu, Zhen-Long Ye, Du-Qing Jiang, Jiang-Chuan He, Yong-Mei Ding, Lin-Fang Li, Sai-Qun Lv, Ying Wang, Hua-Jun Jin, Qi-Jun Qian
Chimeric antigen receptor modified T cell-based immunotherapy is revolutionizing the field of cancer treatment. However, its potential in treating bile duct carcinoma has not been fully explored. Herein, we developed the second-generation mesothelin-targeting chimeric antigen receptor-modified T cells with the 4-1BB co-stimulatory module by the piggyBac transposon system. Mesothelin-targeting chimeric antigen receptor was expressed by 66.0% of mesothelin-targeting chimeric antigen receptor-modified T cells post electrophoretic transfection and stimulation with K562-meso cells; the expressions of activation markers were tested by flow cytometry assay and showed greater activation of mesothelin-targeting chimeric antigen receptor-modified T cells than control T cells (CD107α: 71...
April 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28360017/modification-of-cytokine-induced-killer-cells-with-folate-receptor-alpha-fr%C3%AE-specific-chimeric-antigen-receptors-enhances-their-antitumor-immunity-toward-fr%C3%AE-positive-ovarian-cancers
#10
Shuguang Zuo, Yuqing Wen, Hean Panha, Gongpeng Dai, Liping Wang, Xuequn Ren, Kanda Fu
Folate receptor alpha (FRα) is aberrantly expressed in ovarian cancers but largely absent in normal tissues, and therefore represents an attractive target for immunotherapy. In recent years, modification of T cells with chimeric antigen receptor (CAR) targeting FRα has been reported to improve antitumor immunity of T cells. However, there are limited data regarding CAR-modified cytokine-induced killer (CAR-CIK) cells. In the present study, we modified CIK cells with FRα-specific CARs and investigated their antitumor immunity against ovarian cancers...
May 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28347235/selection-of-single-chain-antibody-fragments-binding-to-the-extracellular-domain-of-4-1bb-receptor-by-phage-display-technology
#11
Salman Bagheri, Mehdi Yousefi, Elmira Safaie Qamsari, Farhad Riazi-Rad, Mohsen Abolhassani, Vahid Younesi, Ruhollah Dorostkar, Ali Akbar Movassaghpour, Zahra Sharifzadeh
The 4-1BB is a surface glycoprotein that pertains to the tumor necrosis factor-receptor family. There is compelling evidence suggesting important roles for 4-1BB in the immune response, including cell activation and proliferation and also cytokine induction. Because of encouraging results of different agonistic monoclonal antibodies against 4-1BB in the treatment of cancer, infectious, and autoimmune diseases, 4-1BB has been suggested as an attractive target for immunotherapy. In this study, single chain variable fragment phage display libraries, Tomlinson I+J, were screened against specific synthetic oligopeptides (peptides I and II) designed from 4-1BB extracellular domain...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28246194/optimized-depletion-of-chimeric-antigen-receptor-t-cells-in-murine-xenograft-models-of-human-acute-myeloid-leukemia
#12
Sarah K Tasian, Saad S Kenderian, Feng Shen, Marco Ruella, Olga Shestova, Miroslaw Kozlowski, Yong Li, April Schrank-Hacker, Jennifer J D Morrissette, Martin Carroll, Carl H June, Stephan A Grupp, Saar Gill
We and others previously reported potent antileukemia efficacy of CD123-redirected chimeric antigen receptor (CAR) T cells in preclinical human acute myeloid leukemia (AML) models at the cost of severe hematologic toxicity. This observation raises concern for potential myeloablation in patients with AML treated with CD123-redirected CAR T cells and mandates novel approaches for toxicity mitigation. We hypothesized that CAR T-cell depletion with optimal timing after AML eradication would preserve leukemia remission and allow subsequent hematopoietic stem cell transplantation...
April 27, 2017: Blood
https://www.readbyqxmd.com/read/28224212/upregulation-of-thioredoxin-1-in-activated-human-nk-cells-confers-increased-tolerance-to-oxidative-stress
#13
Kousaku Mimura, Ley-Fang Kua, Noriko Shimasaki, Kensuke Shiraishi, Shotaro Nakajima, Lim Kee Siang, Asim Shabbir, Jimmy So, Wei-Peng Yong, Koji Kono
Adoptive transfer of immune cells, such as T lymphocytes and NK cells, has potential to control cancer growth. However, this can be counteracted by immune escape mechanisms within the tumor microenvironment, including those mediated by reactive oxygen species (ROS). Here, we determined the levels of anti-oxidant molecules in NK cells and their capacity to overcome ROS-induced immune suppression. We investigated the effect of H2O2 on resting NK cells, IL-2-activated NK cells and NK cells expanded by coculture with the K562 leukemia cell line genetically modified to express membrane-bound IL-15 and 4-1BB ligand (K562-mb15-41BBL)...
February 21, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28197367/targeting-ewing-sarcoma-with-activated-and-gd2-specific-chimeric-antigen-receptor-engineered-human-nk-cells-induces-upregulation-of-immune-inhibitory-hla-g
#14
Sareetha Kailayangiri, Bianca Altvater, Christian Spurny, Silke Jamitzky, Sonja Schelhaas, Andreas H Jacobs, Constanze Wiek, Katharina Roellecke, Helmut Hanenberg, Wolfgang Hartmann, Heinz Wiendl, Susann Pankratz, Jutta Meltzer, Nicole Farwick, Lea Greune, Maike Fluegge, Claudia Rossig
Activated and in vitro expanded natural killer (NK) cells have substantial cytotoxicity against many tumor cells, but their in vivo efficacy to eliminate solid cancers is limited. Here, we used chimeric antigen receptors (CARs) to enhance the activity of NK cells against Ewing sarcomas (EwS) in a tumor antigen-specific manner. Expression of CARs directed against the ganglioside antigen GD2 in activated NK cells increased their responses to GD2+ allogeneic EwS cells in vitro and overcame resistance of individual cell lines to NK cell lysis...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28175613/369%C3%A2-chimeric-antigen-receptors-deficient-in-lck-signaling-require-4-1bb-costimulation-to-expand-in-vivo-resist-regulatory-t-cell-suppression-and-treat-solid-tumors-in-immune-intact-hosts
#15
Carter M Suryadevara, Rupen Desai, Samuel Harrison Farber, Patrick C Gedeon, Adam Swartz, David Snyder, James Herndon, Patrick Healy, Bryan D Choi, Peter Edward Fecci, Luis Sanchez-Perez, John H Sampson
No abstract text is available yet for this article.
August 1, 2016: Neurosurgery
https://www.readbyqxmd.com/read/28129128/aptamer-targeted-attenuation-of-il-2-signaling-in-cd8-t-cells-enhances-antitumor-immunity
#16
Anugraha Rajagopalan, Alexey Berezhnoy, Brett Schrand, Yvonne Puplampu-Dove, Eli Gilboa
Immune responses elicited against cancer using existing therapies such as vaccines or immune stimulatory antibodies are often not curative. One way to potentiate antitumor immunity is to enhance the long-term persistence of anti-tumor CD8(+) T cells. Studies have shown that the persistence of activated CD8(+) T cells is negatively impacted by the strength of interleukin 2 (IL-2) signaling. Here, we used small interfering RNAs (siRNAs) against CD25 (IL-2Rα) to attenuate IL-2 signaling in CD8(+) T cells. The siRNAs were targeted to 4-1BB-expressing CD8(+) T cells by conjugation to a 4-1BB-binding oligonucleotide aptamer...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28115575/the-egr2-targets-lag-3-and-4-1bb-describe-and-regulate-dysfunctional-antigen-specific-cd8-t-cells-in-the-tumor-microenvironment
#17
Jason B Williams, Brendan L Horton, Yan Zheng, Yukan Duan, Jonathan D Powell, Thomas F Gajewski
Although the presence of tumor-infiltrating lymphocytes (TILs) indicates an endogenous antitumor response, immune regulatory pathways can subvert the effector phase and enable tumor escape. Negative regulatory pathways include extrinsic suppression mechanisms, but also a T cell-intrinsic dysfunctional state. A more detailed study has been hampered by a lack of cell surface markers defining tumor-specific dysfunctional TILs, and PD-1 alone is not sufficient. Recently, we identified the transcription factor Egr2 as a critical component in controlling the anergic state in vitro...
February 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28115358/therapeutic-efficacy-of-4-1bb-costimulation-is-abrogated-by-pd-1-blockade-in-a-model-of-spontaneous-b-cell-lymphoma
#18
Sara J McKee, Brianna L Doff, Megan S F Soon, Stephen R Mattarollo
Combinations of mAbs that target various components of T-cell activation/inhibition may work synergistically to improve antitumor immunity against cancer. In this study, we investigated the therapeutic potential of combining an anticancer vaccination strategy with antibodies targeting an immune stimulatory (4-1BB) and immune inhibitory (PD-1) receptor, in a preclinical model of spontaneously arising c-Myc-driven B-cell lymphoma. In Eμ-myc transgenic mice, we reveal that 4-1BB agonistic mAb treatment alone was sufficient to drive antitumor immunity and prevent disease progression in 70% of mice...
March 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28074529/epigenetic-mediated-immune-suppression-of-positive-co-stimulatory-molecules-in-chemoresistant-ovarian-cancer-cells
#19
Ercan Cacan
The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity...
March 2017: Cell Biology International
https://www.readbyqxmd.com/read/28067900/donor-cd19-car-t-cells-exert-potent-graft-versus-lymphoma-activity-with-diminished-graft-versus-host-activity
#20
Arnab Ghosh, Melody Smith, Scott E James, Marco L Davila, Enrico Velardi, Kimon V Argyropoulos, Gertrude Gunset, Fabiana Perna, Fabiana M Kreines, Emily R Levy, Sophie Lieberman, Hillary V Jay, Andrea Z Tuckett, Johannes L Zakrzewski, Lisa Tan, Lauren F Young, Kate Takvorian, Jarrod A Dudakov, Robert R Jenq, Alan M Hanash, Ana Carolina F Motta, George F Murphy, Chen Liu, Andrea Schietinger, Michel Sadelain, Marcel R M van den Brink
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies...
February 2017: Nature Medicine
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